A truncating DUOX2 mutation (R434X) causes severe congenital hypothyroidism

Hakan Cangul 1 , Zehra Aycan 2 , Michaela Kendall 3 , Veysel N. Bas 2 , Yaman Saglam 4 , Timothy G. Barrett 5 , and Eamonn R. Maher 6
  • 1 Department of Medical Genetics, Bahcesehir University School of Medicine, Istanbul, Turkey
  • 2 Division of Paediatric Endocrinology, Dr. Sami Ulus Woman Health, Children Research Hospital, Ankara, Turkey
  • 3 Division of Clinical and Experimental Sciences, Faculty of Medicine, Department of Child Health, Southampton, UK
  • 4 Centre for Genetic Diagnosis, Medical Park Goztepe Hospital, Istanbul, Turkey
  • 5 Centre for Rare Diseases and Personalised Medicine, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK
  • 6 Academic Department of Medical Genetics, University of Cambridge Clinical School, Cambridge, UK
Hakan Cangul, Zehra Aycan, Michaela Kendall, Veysel N. Bas, Yaman Saglam, Timothy G. Barrett and Eamonn R. Maher

Abstract

Mutations in DUOX2 have been reported to cause congenital hypothyroidism (CH), and our aim in this study was to determine the genetic basis of CH in two affected individuals coming from a consanguineous family. Because CH is usually inherited in autosomal recessive manner in consanguineous/multicase families, we adopted a two-stage strategy of genetic linkage studies and targeted sequencing of the candidate genes. First, we investigated the potential genetic linkage of the family to any known CH locus using microsatellite markers and then screened for mutations in linked genes by Sanger sequencing. The family showed potential linkage to DUOX2 locus and we detected a nonsense mutation (R434X) in both cases and the mutation segregated with disease status in the family. This study highlights the importance of molecular genetic studies in the definitive diagnosis and classification of CH, and it also suggests a new clinical testing strategy using next-generation sequencing in all primary CH cases.

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